Imaging is often fundamental to screening, detection, diagnosis and staging of cancer. It also plays significant roles in cancer treatment planning, and in monitoring patients during and after therapy. Imaging also is a vital tool in cancer research, where it is used to improve our understanding of cancer biology and in the longitudinal evaluation of the effects of new therapeutic strategies in preclinical studies. Further development of existing imaging technologies, as well as the invention or discovery of new ones, is critical in the fight against cancer. Improvements in imaging technologies will help us detect disease earlier, stage cancer more accurately, select more appropriate treatments and provide earlier feedback when a treatment is not working. Imaging will become further engrained in interventional cancer therapies, especially in surgery where there is an urgent need for better methods to guide surgeons during resection to avoid functional areas and achieve cancer-free margins wherever possible. We also expect imaging research to enhance cancer imaging through faster and lower cost imaging, and by reducing radiation dose, thus making imaging more widely accessible, and enhancing patient comfort and safety. In the laboratory setting, instruments capable of improved structural, functional and molecular characterization of tumors in appropriate animal models, as well as the development of new imaging biomarkers, often linked with targeted therapies, will be critical in providing the foundation for these advances. Thus further investments in cancer imaging at all levels are likely to yield a high pay off. Molecular imaging with optical contrast or radiotracers provides some of the highest sensitivity in vivo assays available, and offers a rich source of contrast mechanisms. In this proposal we build on our 25-year track record in the field of biomedical imaging and propose to exploit new opportunities for cancer imaging and cancer theranostics that lie at the intersection of photonics and radiation science. We propose initial projects that 1) offer the prospect of high-resolution optical imaging of radionuclides using ultrasound-modulation of Cerenkov luminescence; 2) enable targeted delivery of light to tumors deep inside the body allowing phototherapy to be applied as a systemic treatment for metastatic disease and 3) exploit the instantaneous generation of optical Cerenkov photons in positron emission tomography (PET) detectors with the goal of significantly improving the timing resolution and the signal-to-noise ratio in PET imaging. The approach in this proposal is to create and support a research environment that allows our laboratory to rapidly test and develop new ideas, with a goal of efficiently developing innovative cancer imaging and therapeutic strategies that will either directly (through improved diagnosis, staging or therapy), or indirectly (via contributions o cancer research) benefit cancer patients.